5-Lipoxygenase is the first enzyme in the pathway leading to the biosynthesis of leukotrienes (LTs). In the course of this pathway or "cascade", arachidonic acid, the 5-lipoxygenase substrate from which leukotriene (LT) products are derived, is first converted to 5-hydroperoxy-eicosatetraenoic acid (5-HPETE) and subsequently reduced to 5-hydroxyeicosatetraenoic acid (5-HETE) or converted to LTA.sub.4. The reactive leukotriene intermediate LTA.sub.4 is enzymatically hydrated to LTB.sub.4 or conjugated to the tripeptide glutathione to produce LTC.sub.4. LTA.sub.4 can also be hydrolyzed nonenzymatically to form two isomers of LTB.sub.4. Successive proteolytic cleavage steps convert LTC.sub.4 to LTD.sub.4 and LTE.sub.4. Other products resulting from further oxygenation steps have also been described. (See Serhan, C. N., Hamberg, M., and Samuelsson, B., Lipoxins: Novel Series of Biologically Active Compounds Formed from Arachidonic Acid in Human Leukocytes, Proceedings of the National Academy of Sciences, USA, 81:5335 (1985)).
Products of the 5-lipoxygenase cascade are extremely potent substances which produce a wide variety of biological effects, often in the nanomolar to picomolar concentration range. (Sirois, P., "Pharmacology of the Leukotrienes", Advances in Lipid Research, R. Paoletti & D. Kritchevesky, eds., Academic Press, 21:79 (1985.)) The remarkable potencies and diversity of actions of products of the 5-lipoxygenase pathway have led to the suggestion that they play important roles in a variety of diseases. The presence of LTs A.sub.4 -E.sub.4 has been associated with a number of disease states, including asthma, allergic rhinitis, rheumatoid arthritis, gout, psoriasis, inflammatory disorders of the skin, acne, atherosclerosis, adult respiratory distress syndrome, inflammatory bowel disease, endotoxin shock, ischemia induced myocardial injury, and central nervous pathophysiology.
The enzyme 5-lipoxygenase catalyzes the first step leading to the biosynthesis of all the leukotrienes, and inhibition of this enzyme is therefore likely to limit the effects of these potent mediators of numerous pathophysiological processes. Agents which block or modulate the activity of lipoxygenase enzymes thus represent a promising class of therapeutic agents for use in the treatment of diseases involving leukotriene pathogenesis. (Brooks, D. W., Bell, R. L., and Carter, G. W., Chapter 8: Pulmonary and Antiallergy Agents, Annual Reports in Medicinal Chemistry, Allen, R. C., ed., Academic Press (1988)). Examples of 5-lipoxygenase inhibitors known to the art are: AA-861, disclosed in U.S. Pat. No. 4,393,075,issued July 12, 1983 to Terro et al.; pyrazolopyridines, disclosed in the European Patent Application of Iriburn et al., Ser. No. 121,806, published Oct. 17, 1984; arachidonyl hydroxamic acid, disclosed in Corey et al., J. Am. Chem. Soc., 106:1503 (1984) and in the European Patent Application of Nelson, Ser. No. 104,468, published Apr. 4, 1984; BW-755C, disclosed in Radmark et al., FEBS Letters, 110:213 (1980); nordihydroguaiaretic acid, disclosed in Marris et al., Prostaglandins, 19:371 (1980); Rev-5901, disclosed in Coutts, Meeting Abstract 70, Prostaglandins and Leukotrienes '84; benzoxaprofen, disclosed in Walker, Pharm. Pharmacol., 31:778 (1979); and hydroxamic acids, disclosed in U.S. Pat. Nos. 4,608,390 and 4,623,661, issued Aug. 16 and Nov. 18, 1986, respectively.